Magnetic Resonance Imaging (MRI) is an imaging technique used in medicine. In this technique, images are obtained by applying a strong magnetic field, a magnetic-field gradient, and frequency-matched radio frequency (RF) pulses to a subject or sample. During the imaging process, atomic nuclei in the subject or sample, which have a magnetic moment and which are mostly protons, become excited by the RF radiation. When the RF pulse is stopped, relaxation of the excited nuclei causes emission of an RF signal that is detected. This signal is referred to as the free-induction decay (FID) response signal. As a result of applied magnetic-field gradients, the frequencies in this RF signal contain spatial information that are used to construct a gray scale image.
Since protons are the most abundant and sensitive nuclei in biological tissues, a majority of medical applications of MRI utilize images of protons. These MRI images primarily reflect the distribution of water in the subject (e.g., a human body) or sample, since the protons in biological tissue are present mainly as water. MRI images have an appearance which is similar to X-ray computerized tomography (CT) scan images, but MRI images are based on differences in water content and differences in relaxation rates of water in various body tissues rather than on differences in the absorption of X-rays between various tissues of the body.
More specifically, in MR imaging the subject or sample is placed in a static magnetic field (a biasing field) and then excitation signals are applied to induce a response. Time varying magnetic fields (gradient fields) permit localized points in the tissue volume to be addressed. Sequences of radio frequency pulses excite nuclei that respond at specific RF pulse frequencies, typically reorienting the magnetic moments and spin axes of the nuclei away from their initial orientation in the biasing field. Following a pulse that reorients the magnetic moments of adjacent nuclei, the nuclei relax over a period of time (T1) and return to their original alignment relative to the biasing field. This time describes the return to equilibrium magnetization in the longitudinal direction and is called the spin-lattice relaxation time. The specific time period varies with the type of nuclei, the incident magnetic fields, and the amplitude of the excitation.
In addition, adjacent nuclei of the same element, subjected locally to the same biasing field, gradient field, and excitation conditions, have magnetic moments that tend to process synchronously, in phase with one another, which persists for a limited time after the excitation is discontinued. The phase synchronized spins of a group of adjacent nuclei together produce a detectable signal at the resonant frequency. When the phases are random, the net emitted signal is zero. Thus, the amplitude of the signal varies with the concentration of nuclei that are processing in phase. The signal decays over a period of time (T2) as the nuclei fall out of phase with one another. This time describes the return to equilibrium of the transverse magnetization and is called the spin-spin relaxation time. This time period is related to the type of nuclei, the bias conditions, excitation, and the temperature of the sample being imaged.
An echo decay experiment is often used to measure this T2 decay constant. Pulse sequences are designed to include pulses that are synchronous with nuclei of a particular element and/or that affect the precession and phase relationships of adjacent nuclei. Signals are received along a phase encoding axis and are sampled, digitized, and processed by Fourier transforms to convert so-called k-space data to spatially resolved amplitude data. The resulting values can distinguish the nuclei of one element from another in a three-dimensional matrix of voxel locations. The values are stored in a memory referenced to spatial location in the imaged volume and can be displayed in slices or projections, enabling the practitioner to visualize the tissues based on the detected concentrations of elements therein.
MRI visualization is based on measuring differences in T1 and T2 decay (and derivatives thereof) resulting from differences in the amount of water and/or salts, ions, elements, macromolecules, etc. in tissues throughout the volume analyzed. However, when a difference in intensity caused by the contrast between different tissues (or between healthy and diseased tissues) is not sufficient to obtain satisfactory clinical information, MRI contrast agents are used to improve visualization.
A contrast agent is a substance that, when administered to a subject, increases the image contrast (e.g., provides contrast enhancement) between a chosen target, tissue, or organ and the rest of the field of the image (e.g., the remaining areas of the body), or between healthy and diseased tissues. Contrast agents possess permanent magnetic dipoles, which influence the relaxation processes of the nearby water protons and so lead to a local change of the image contrast. In particular, the relaxation rates of water in body tissue may be increased by adding paramagnetic metal ions (ions with unpaired electrons) to the tissue. The unpaired electrons in these metals greatly increase the relaxation rates of nearby water protons. Thus, where paramagnetic metals are taken up in a greater amount by certain tissues, the relaxation rates of water protons in those tissues are increased relative to tissues that take up a lesser amount of the metal. These tissues appear light in MRI images. A substance, such as one of these paramagnetic metals, which causes tissue to appear lighter or darker in MRI images as a result of its presence is termed a contrast agent. Desirable properties for a contrast agent include high relaxivity, low toxicity, and the ability to distinguish different tissues or pathologies. Gadolinium (which causes a decrease in signal on T2-weighted images and an increase in signal on T1-weighted images) and superparamagnetic iron-oxide (which improves tumor contrast by decreasing the T2 signal in normal tissue) are known conventional contrast agents.
Contrast agents can be introduced to improve the extent to which pertinent tissue types and tissue structures can be distinguished, in particular because the contrast agents assume different concentrations in different tissues. For example, vascular contrast agents improve the visualization of the vascular system by altering the contrast of the vascular system relative to the surrounding tissues, usually by brightening (hyper-intensifying) the vascular system (e.g., the blood). In addition, tissues also can be distinguished with respect to differences in the rates at which a perfused contrast agent diffuses into the tissues and the image contrast obtained by the contrast agent fades away in successive MR images taken over a period of time. Moreover, some contrast agents are responsive to the physical environment (e.g., pH, calcium ion concentration, temperature) or to biomolecular markers (e.g., an antibody, a nucleic acid, a protein, a metabolite, hemoglobin, choline, creatine, lactate, etc.) present in biological systems.
MRI using a contrast agent is a grayscale technique, e.g., it results in the visualization of variations along a one-dimensional continuum of intensities. However, because MRI is prone to imaging artifacts and many factors influence image intensity, contrast interpretation on MRI molecular imaging is difficult. The art would benefit from MR imaging in multiple colors that increases the information content of the MRI image, and thus improves the diagnostic power of the technique.
Compared to conventional technologies that assign colors to tissues, colorizing contrast agents has presented unique challenges in the art because many properties that influence signal intensity, such as T1 and T2, vary with concentration and contrast agent localization. In addition, distinguishing different contrast agents that are co-localized is another challenge because the agents work by influencing their molecular environment without emitting an intrinsic signal.